Abstract

Background Despite extensive research and recommendations regarding
the optimal prescription of antipsychotic drugs, polypharmacy and excessive
dosing still prevail.

Aims To identify the factors associated with the polypharmacy and
excessive dosing phenomena.

Method We studied 139 patients with schizophrenia, in 19 acute
psychiatric units in Japanese hospitals, who were due to be discharged between
October and December 2003. We examined patient characteristics, nurses’
requests, and psychiatrists’ characteristics and perceptions of
prescribing practice and algorithms.

Results Polypharmacy and excessive dosing were observed in 96 cases.
Logistic regression analysis revealed that the use of multiple medications and
excessive dosing were influenced by the psychiatrist’s scepticism
towards the use of algorithms, nurses’ requests for more drugs and the
patient’s clinical condition.

Conclusions Educational interventions are necessary for
psychiatrists and nurses to follow evidence-based guidelines or
algorithms.

Polypharmacy involves the concomitant administration of two or more drugs.
Excessive dosing refers to doses greater than optimal daily dosage of between
300 and 1000 mg of chlorpromazine equivalent
(Lehman & Steinwachs,
1998). Despite extensive research and recommendations as to the
optimal prescription of antipsychotics, polypharmacy and excessive dosing are
still widely prevalent in clinical practice in Canada
(Procyshyn et al,
2001), East Asia (Bitter et
al, 2003; Chong et
al, 2004) and the USA
(Diaz & de Leon, 2002;
Bitter et al, 2003;
Sohler et al, 2003).
Polypharmacy is strongly associated with excessive dosing
(Lelliott et al,
2002). Although several causes of polypharmacy and excessive
dosing have been proposed, few studies have explored psychiatrists’
perceptions of prescribing practice since the establishment of Benson’s
conceptual approach as a three-stage decision-making process: the
psychiatrist’s decision to prescribe any psychopharmaceutical, the
decision to prescribe an antipsychotic drug and the determination of
antipsychotic drug dosage (Benson,
1983). In this study, we aimed to identify the factors associated
with the polypharmacy and excessive dosing phenomena. We examined patient
characteristics, nurses’ requests for drugs, the characteristics of the
prescribing psychiatrists and their perceptions of prescribing practices and
algorithms in Japan.

METHOD

Participants

We invited all public and private hospitals with acute psychiatric care
units (as defined by the Japanese reimbursement system) to participate in the
study. Acute psychiatric care units under this reimbursement system have
strict criteria: the hospitals have to participate in the regional psychiatric
emergency system; the levels of staffing are more than twice those of general
psychiatric units; at least one seclusion room should be available; more than
40% of patients come from the community; and the patients should be discharged
within the shortest possible period. A total of 19 hospitals (3 public and 16
private) agreed to participate in the study. There were no significant
differences in the characteristics of these hospitals, such as size, ownership
and the number of beds.

All the patients with schizophrenia discharged from the participating units
between 1 October and 25 December 2003 were invited to take part in the study.
Of 251 patients, 179 (71.3%) agreed to participate and provided written
informed consent, a sample size considered to be sufficient to give an
overview of the prescribing patterns during the study period. Thirty-four
patients were eliminated from the analysis because of missing data, and a
further six patients were eliminated because they had not been prescribed
antipsychotics. Thus, we used data from 139 patients for our analysis. There
was no significant difference in the age and gender of the patients selected
for inclusion and exclusion.

The study was approved by the institutional review board of the Japanese
National Centre of Neurology and Psychiatry and also by the institutional
review board or board of directors of each participating hospital. Research
coordinators collected patient information from the participating hospitals
without identifying the patients.

Patient characteristics

We defined a standard dosage group comprising patients who were receiving
one antipsychotic drug with a dosage of less than 1000 mg chlorpromazine
equivalent. The remaining patients constituted the non-standard dosage group.
We asked psychiatrists about the clinical variables of the patients, including
psychiatric diagnosis and length of illness. All the patients had a clinical
diagnosis of schizophrenia based on DSM–IV criteria
(American Psychiatric Association,
1994). Psychiatrists also rated the patients on the Global
Assessment of Functioning (GAF; American
Psychiatric Association, 1994) scale both at admission and at
discharge. Lower GAF scores indicate greater disability. Nurses provided
patient demographic variables and reported the use of seclusion and physical
restraint during in-patient care.

Psychiatrist characteristics and prescribing perceptions

We asked the 78 psychiatrists treating the 139 patients to provide
information on their demographic variables (age and gender), medical
qualifications, length of clinical experience, and perceptions of prescribing
practice and dosing algorithms.

The psychiatrists were asked to describe their perceptions of prescribing
practice and algorithms before the patients were recruited. Questions on
prescribing practice included cost considerations, familiarity with the
research literature and the importance of ‘experience-based’
prescribing. Perceptions of algorithms were elicited by questions such as ‘
I understand the contents of an algorithm’, ‘An algorithm
disregards individual patient characteristics’, ‘I doubt the
validity and evidence of an algorithm’ and ‘I think that an
algorithm is necessary for clinical practice’. Each item was rated using
a four-point Likert scale (1, strongly disagree; 2, disagree; 3, agree; 4,
strongly agree). Japanese translations of algorithms and guidelines used in
the UK (Taylor et al,
2001) and the USA (American
Psychiatric Association, 1997) were available to these
psychiatrists in addition to algorithms developed in Japan.

Nurses’ requests for drugs

The nurses completed a questionnaire survey. The questionnaire asked
whether they believed that it was necessary to increase the current dosage of
medication or add another drug; to decrease the current dosage or number of
drugs; or to change the current drug. We also asked the nurses to indicate the
reason why they believed a change was necessary in each case.

Statistical analysis

All dosages of antipsychotic drugs were converted into chlorpromazine
equivalents to facilitate comparisons
(Bezchlibnyk-Butler & Jeffries,
1998; Inagaki et al,
1999). We used t-tests to compare mean scores and
chi-squared tests to compare categorical data. The Mann–Whitney test was
used to compare the rank data between the standard and non-standard dosage
groups. Multiple logistic regression analysis was used to assess the
independent and interactive effects of the multiple factors that could
contribute to prescribing practice. After we examined the relationship of each
variable in the two prescribing practice groups, we included only the
significant variables when comparing the two groups in the logistic regression
analysis. All tests were two-tailed. Analyses were performed using the
Statistical Package for the Social Sciences, version 11.0.

RESULTS

Table 1 shows the patterns
of prescription of antipsychotic drugs. There were 37 patients (27%) in the
standard dosage group: 29 of the 37 were taking atypical antipsychotics. Of
the 102 patients (73%) in the non-standard dosage group, 96 were taking more
than one drug, 32 of whom were also prescribed excessive dosages. In the
non-standard dosage group, 57 patients were given both typical and atypical
antipsychotics simultaneously.

The psychiatrists’ mean age was 41.3 years (s.d.=10.7), with 12.9
years’ (s.d.=10.8) experience in psychiatric services. Of the 78
psychiatrists, 50 (64%) were designated psychiatrists with extra training;
these individuals were qualified to make the decision for compulsory admission
under the Mental Health and Welfare Law of Japan 1995. Regarding the
psychiatrists’ demographic variables, medical qualifications, length of
clinical experience and perceptions of prescribing practice, no significant
difference was observed between the standard and non-standard dosage groups.
There were, however, significant differences in the psychiatrists’
perceptions of algorithms. Psychiatrists caring for patients in the
non-standard dosage group were significantly more likely to agree with the
statement ‘I doubt the validity and evidence of an algorithm’
(z=–2.95, P=0.003) and more likely to disagree with
the statement ‘I think that an algorithm is necessary for clinical
practice’ (z=–2.49, P=0.013) compared with those
in the standard dosage group.

Patient characteristics are shown in
Table 2. There was no
significant difference in age or gender between the standard and non-standard
dosage groups. The non-standard dosage group had a significantly longer
duration of illness than the standard dosage group. There was no significant
difference in involuntary admission or the use of physical restraint during
in-patient care. The GAF scores at admission did not differ significantly,
whereas the GAF score of the non-standard dosage group at discharge was
significantly lower than that of the standard dosage group.

Forty-nine (59%) of the 83 nurses caring for our 139 patients were men. The
nurses’ mean age was 35.3 years (s.d.=9.3), and they had an average of
9.4 years’ (s.d.=7.3) experience in psychiatric services. Nurses
endorsed the statement that ‘I would like to ask a psychiatrist to
increase the current dosage or add another drug’ for 39 patients. The
proportion of nurses agreeing with this statement was significantly greater in
the non-standard dosage group than in the standard dosage group. The reasons
nurses requested a change in treatment included ‘no improvement in
symptoms’ (24 patients; 62%), ‘deterioration in symptoms’ (9
patients; 23%), ‘beyond nursing care’ (4 patients; 10%) and ‘
other’ (2 patients, 5%). There was no significant difference
between the standard and non-standard dosage groups with regard to the reasons
for the desired alteration in drug treatment.

Logistic regression analysis revealed that the non-standard dosage group
was significantly more likely to have both a longer duration of illness and a
lower level of functioning as evaluated by the GAF scale
(Table 3). The analysis also
showed that the psychiatrists’ perceptions of algorithms were associated
with polypharmacy and excessive dosing. Nurses in the non-standard dosage
group were more likely to believe that their patients needed more drugs than
those in the standard dosage group.

DISCUSSION

Antipsychotic polypharmacy and excessive dosing continue to be used for the
treatment of schizophrenia in acute psychiatric care units despite current
recommendations. The results indicate that polypharmacy and excessive dosing
are associated with both psychiatrists’ perceptions of the use of
algorithms and nurses’ requests for more drugs, as well as the clinical
variables of the patients.

Methodological considerations

We examined the factors influencing the patterns of prescription of
antipsychotics using three explanatory variables: patient characteristics,
nurses’ requests for drugs and psychiatrists’ perceptions of best
prescribing practice and algorithms. The psychiatrists’ perceptions were
subjective measures and we did not conduct an objective assessment of this
variable. Also, we were not able to examine subjective patient outcomes, such
as satisfaction with medication and quality of life, although the
psychiatrists rated the patients’ level of functioning using the GAF
score. Ideally, one should examine the relationship between prescribing
patterns and the long-term outcomes of patients.

Every acute psychiatric care unit had the same staffing ratio of patients
to nurses. The size and ownership of the hospitals did not differ between the
standard and non-standard dosage groups; however, we did not examine
additional institutional characteristics and staffing, owing to substantial
missing and inappropriate data for analysis. This study was not a
retrospective review of patient records; rather, we obtained prospective data
at the point when discharge was planned. Furthermore, the patient, nurse and
psychiatrist data were collected separately and matched later. Thus, we were
able to analyse prescribing patterns for individual patients rather than using
a group analysis.

The number of participating hospitals was small because we used strict
recruitment criteria. In Japan, there are still many psychiatric care units
that are similar to rehabilitation units in Western countries. As Japan is now
in a transitional period from long-term to acute hospital care, various
measures are employed to shorten the patients’ length of stay. One such
measure is that an acute psychiatric care unit is strictly defined in the
reimbursement system. We used this criterion to select our hospital sample;
however, only a limited number of hospitals have been officially designated as
acute psychiatric care units. Therefore, our sample might not be nationally
representative of all hospitals in Japan with acute psychiatric care units. To
reduce the burden on participating hospitals the study period was only 2
months, and because of this the number of patients who met the diagnostic
criteria during that period was limited.

Benefits and risks of combination therapy

It is not appropriate that polypharmacy and high-dosage prescribing should
always be viewed as a poor prescribing pattern, because using more than one
antipsychotic drug can be effective in some patients, and different
antipsychotics have different effects on different symptoms of psychosis
(Taylor, 2002). The Royal
College of Psychiatrists’ consensus statement in the UK
(Royal College of Psychiatrists,
1993) suggests that there are some justifiable cases of temporary
polypharmacy, including making a gradual change from one drug to another
(Thompson, 1994). Although
sulpiride augmentation of clozapine is suggested to be of benefit by a
randomised controlled trial (Shiloh et
al, 1997), evidence for the efficacy of combining
antipsychotics is limited (Freudenreich & Goff, 2002). There are potential adverse effects, some of
which are even life-threatening (Centorrino
et al, 2004). Polypharmacy is associated with early death
(Waddington et al,
1998). Reilly et al
(2000) reported that use of
thioridazine was a predictor of QTc prolongation, and Ray et
al (2001) suggested that
even moderate doses of antipsychotics would increase the risk of sudden
cardiac death. Asian patients are more vulnerable to side-effects and might
require less antipsychotic medication than European patients
(Ungvari et al, 1996;
Chong et al,
2004).

Despite these known risks, polypharmacy and excessive dosing with
antipsychotics persist in Japan. An inadequate knowledge of pharmacology may
underlie this phenomenon (Kingsbury et
al, 2001; Procyshyn
et al, 2001). Based on a questionnaire regarding the use
of depot formulations, Patel et al
(2003) suggested that
psychiatrists’ knowledge about maintenance medication was positively
associated with attitudes toward the medication.

Concurrent prescription of atypical and typical antipsychotics is not
recommended in principle by the National Institute for Clinical Excellence in
the UK (National Institute for Clinical
Excellence, 2002). It rarely improved outcomes, while it increased
use of anticholinergic medication (Taylor
et al, 2000). In our study, we found the combination of
typical and atypical antipsychotics to be a popular prescribing pattern. Four
atypical antipsychotics are available in Japan, including risperidone (since
1996), perospirone, quetiapine and olanzapine (since 2001), but clozapine has
not been approved yet. The results suggest that many psychiatrists do not
fully understand the mechanisms and advantages of atypical antipsychotics, and
do not want to change their prescribing patterns.

As in the investigation by Harrington et al
(2002) of the issue of
medication given at the discretion of nurses, most nurses requested higher
doses of medication for the reason of patient symptoms in our study (85%). The
process of psychiatrists’ agreement is unknown; however, there are two
possibilities: one is that a patient still has a psychosis, and the other is
that they wish to control patient behaviour. Scepticism towards algorithms and
scientific evidence still exists among psychiatrists, which leads to their
relying solely on clinical experience when prescribing antipsychotic
medication. Consequently, psychiatrists who are sceptical about algorithms are
potential targets for educational intervention. Also, educational programmes
detailing scientific advances can be effective for healthcare providers,
including psychiatrists and nurses.

Future interventions

Education, guidelines and algorithms are mentioned in the research
literature as ways to avoid irrational polypharmacy and high doses for the
purpose of unnecessary sedation (Ungvari
et al, 1997; Lehman & Steinwachs, 1998; Covell
et al, 2002). In fact, the introduction of educational
programmes and guidelines is reportedly effective
(Avorn et al, 1992;
Grimshaw & Russell, 1993),
but it also was reported that the degree of performance improvement varied
(Grimshaw & Russell, 1993)
and that systematic practice-based interventions and outreach visits were
necessary (Davis et al,
1995). McCue et al
(2003) suggested that a
rational strategy for prescribing can lead to a decrease in adverse drug
reactions and an improvement in patient outcomes, even when using more than
one antipsychotic drug.

We did not examine the effects of educational intervention in this study.
An intervention study is necessary to assess the feasibility and impact of
implementing an evidence-based medication algorithm; we plan to include this
in our next research protocol.

Clinical Implications and Limitations

CLINICAL IMPLICATIONS

Prescribing patterns that include antipsychotic polypharmacy and excessive
dosing persist in clinical practice in Japan.

Major associated factors were psychiatrists’ perceptions of
medication algorithms and nurses’ requests for more drugs, as well as
the length of illness and level of functioning of patients.

Educational interventions are necessary for psychiatrists and nurses to
follow evidence-based guidelines or algorithms.

LIMITATIONS

The numbers of participating hospitals and patients were limited owing to
strict inclusion criteria and a short research period.

Subjective patient outcomes were not examined.

There was no intervention to improve prescribing practice.

Acknowledgments

The study was supported in part by the Ministry of Health, Labour and
Welfare, Japan. The opinions expressed in this article are those of the
authors and do not represent the official views of the Ministry.

Taylor, D., Mace, S., Mir, S., et al
(2000) A prescription survey of the use of atypical
antipsychotics for hospital inpatients in the United Kingdom.
International Journal of Psychiatry in Clinical
Practice, 4, 41
-46.